Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively neutral, a small proportion ...will affect functional properties and may alter infectivity, disease severity or interactions with host immunity. The emergence of SARS-CoV-2 in late 2019 was followed by a period of relative evolutionary stasis lasting about 11 months. Since late 2020, however, SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations, in the context of 'variants of concern', that impact virus characteristics, including transmissibility and antigenicity, probably in response to the changing immune profile of the human population. There is emerging evidence of reduced neutralization of some SARS-CoV-2 variants by postvaccination serum; however, a greater understanding of correlates of protection is required to evaluate how this may impact vaccine effectiveness. Nonetheless, manufacturers are preparing platforms for a possible update of vaccine sequences, and it is crucial that surveillance of genetic and antigenic changes in the global virus population is done alongside experiments to elucidate the phenotypic impacts of mutations. In this Review, we summarize the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets.
Abstract
The small subunit ribosomal RNA gene (16S rRNA) has been successfully used to catalogue and study the diversity of prokaryotic species and communities but it offers limited resolution at the ...species and finer levels, and cannot represent the whole-genome diversity and fluidity. To overcome these limitations, we introduced the Microbial Genomes Atlas (MiGA), a webserver that allows the classification of an unknown query genomic sequence, complete or partial, against all taxonomically classified taxa with available genome sequences, as well as comparisons to other related genomes including uncultivated ones, based on the genome-aggregate Average Nucleotide and Amino Acid Identity (ANI/AAI) concepts. MiGA integrates best practices in sequence quality trimming and assembly and allows input to be raw reads or assemblies from isolate genomes, single-cell sequences, and metagenome-assembled genomes (MAGs). Further, MiGA can take as input hundreds of closely related genomes of the same or closely related species (a so-called 'Clade Project') to assess their gene content diversity and evolutionary relationships, and calculate important clade properties such as the pangenome and core gene sets. Therefore, MiGA is expected to facilitate a range of genome-based taxonomic and diversity studies, and quality assessment across environmental and clinical settings. MiGA is available at http://microbial-genomes.org/.
In late 2020, after circulating for almost a year in the human population, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibited a major step change in its adaptation to humans. ...These highly mutated forms of SARS-CoV-2 had enhanced rates of transmission relative to previous variants and were termed 'variants of concern' (VOCs). Designated Alpha, Beta, Gamma, Delta and Omicron, the VOCs emerged independently from one another, and in turn each rapidly became dominant, regionally or globally, outcompeting previous variants. The success of each VOC relative to the previously dominant variant was enabled by altered intrinsic functional properties of the virus and, to various degrees, changes to virus antigenicity conferring the ability to evade a primed immune response. The increased virus fitness associated with VOCs is the result of a complex interplay of virus biology in the context of changing human immunity due to both vaccination and prior infection. In this Review, we summarize the literature on the relative transmissibility and antigenicity of SARS-CoV-2 variants, the role of mutations at the furin spike cleavage site and of non-spike proteins, the potential importance of recombination to virus success, and SARS-CoV-2 evolution in the context of T cells, innate immunity and population immunity. SARS-CoV-2 shows a complicated relationship among virus antigenicity, transmission and virulence, which has unpredictable implications for the future trajectory and disease burden of COVID-19.
Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled ...haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average minimum contig length needed to cover 50% of the genome: 26 million base pairs) integrate all forms of genetic variation, even across complex loci. We identified 107,590 structural variants (SVs), of which 68% were not discovered with short-read sequencing, and 278 SV hotspots (spanning megabases of gene-rich sequence). We characterized 130 of the most active mobile element source elements and found that 63% of all SVs arise through homology-mediated mechanisms. This resource enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1526 expression quantitative trait loci as well as SV candidates for adaptive selection within the human population.
The complete assembly of each human chromosome is essential for understanding human biology and evolution
. Here we use complementary long-read sequencing technologies to complete the linear assembly ...of human chromosome 8. Our assembly resolves the sequence of five previously long-standing gaps, including a 2.08-Mb centromeric α-satellite array, a 644-kb copy number polymorphism in the β-defensin gene cluster that is important for disease risk, and an 863-kb variable number tandem repeat at chromosome 8q21.2 that can function as a neocentromere. We show that the centromeric α-satellite array is generally methylated except for a 73-kb hypomethylated region of diverse higher-order α-satellites enriched with CENP-A nucleosomes, consistent with the location of the kinetochore. In addition, we confirm the overall organization and methylation pattern of the centromere in a diploid human genome. Using a dual long-read sequencing approach, we complete high-quality draft assemblies of the orthologous centromere from chromosome 8 in chimpanzee, orangutan and macaque to reconstruct its evolutionary history. Comparative and phylogenetic analyses show that the higher-order α-satellite structure evolved in the great ape ancestor with a layered symmetry, in which more ancient higher-order repeats locate peripherally to monomeric α-satellites. We estimate that the mutation rate of centromeric satellite DNA is accelerated by more than 2.2-fold compared to the unique portions of the genome, and this acceleration extends into the flanking sequence.
Surface antigens of pathogens are commonly targeted by vaccine-elicited antibodies but antigenic variability, notably in RNA viruses such as influenza, HIV and SARS-CoV-2, pose challenges for control ...by vaccination. For example, influenza A(H3N2) entered the human population in 1968 causing a pandemic and has since been monitored, along with other seasonal influenza viruses, for the emergence of antigenic drift variants through intensive global surveillance and laboratory characterisation. Statistical models of the relationship between genetic differences among viruses and their antigenic similarity provide useful information to inform vaccine development, though accurate identification of causative mutations is complicated by highly correlated genetic signals that arise due to the evolutionary process. Here, using a sparse hierarchical Bayesian analogue of an experimentally validated model for integrating genetic and antigenic data, we identify the genetic changes in influenza A(H3N2) virus that underpin antigenic drift. We show that incorporating protein structural data into variable selection helps resolve ambiguities arising due to correlated signals, with the proportion of variables representing haemagglutinin positions decisively included, or excluded, increased from 59.8% to 72.4%. The accuracy of variable selection judged by proximity to experimentally determined antigenic sites was improved simultaneously. Structure-guided variable selection thus improves confidence in the identification of genetic explanations of antigenic variation and we also show that prioritising the identification of causative mutations is not detrimental to the predictive capability of the analysis. Indeed, incorporating structural information into variable selection resulted in a model that could more accurately predict antigenic assay titres for phenotypically-uncharacterised virus from genetic sequence. Combined, these analyses have the potential to inform choices of reference viruses, the targeting of laboratory assays, and predictions of the evolutionary success of different genotypes, and can therefore be used to inform vaccine selection processes.
Monoclonal antibodies (mAbs) offer a treatment option for individuals with severe COVID-19 and are especially important in high-risk individuals where vaccination is not an option. Given the ...importance of understanding the evolution of resistance to mAbs by SARS-CoV-2, we reviewed the available in vitro neutralization data for mAbs against live variants and viral constructs containing spike mutations of interest. Unfortunately, evasion of mAb-induced protection is being reported with new SARS-CoV-2 variants. The magnitude of neutralization reduction varied greatly among mAb-variant pairs. For example, sotrovimab retained its neutralization capacity against Omicron BA.1 but showed reduced efficacy against BA.2, BA.4 and BA.5, and BA.2.12.1. At present, only bebtelovimab has been reported to retain its efficacy against all SARS-CoV-2 variants considered here. Resistance to mAb neutralization was dominated by the action of epitope single amino acid substitutions in the spike protein. Although not all observed epitope mutations result in increased mAb evasion, amino acid substitutions at non-epitope positions and combinations of mutations also contribute to evasion of neutralization. This Review highlights the implications for the rational design of viral genomic surveillance and factors to consider for the development of novel mAb therapies.
Climate change has exacerbated the occurrence of large‐scale sea surface temperature anomalies, or marine heatwaves (MHWs)—extreme phenomena often associated with mass mortality events of marine ...organisms. Using a combination of citizen science and federal data sets, we investigated the causal mechanisms of the 2014/2015 die‐off of Cassin's Auklets (Ptychoramphus aleuticus), a small zooplanktivorous seabird, during the NE Pacific MHW of 2013–2015. Carcass deposition followed an effective reduction in the energy content of mesozooplankton, coincident with the loss of cold‐water foraging habitat caused by the intrusion of the NE Pacific MHW into the nearshore environment. Models examining interannual variability in effort‐controlled carcass abundance (2001–2014) identified the biomass of lipid‐poor zooplankton as the dominant predictor of increased carcass abundance. In 2014, Cassin's Auklets dispersing from colonies in British Columbia likely congregated into a nearshore band of cooler upwelled water and ultimately died from starvation following the shift in zooplankton composition associated with onshore transport of the NE Pacific MHW. For Cassin's Auklets, already in decline due to ocean warming, large‐scale and persistent MHWs might represent a global population precipice.
Plain Language Summary
During the winter of 2014/2015, thousands of Cassin's Auklets, a small seabird that breeds in the NE Pacific, were found dead on beaches from California to British Columbia, Canada. We show that wide‐scale starvation was due to a change in food quality associated with warmer ocean temperatures preceding and during the die‐off. This research highlights that more frequent and intense ocean warming events may have complex impacts on food webs with population consequences for marine predators, particularly seabirds such as Cassin's Auklets.
Key Points
During the winter of 2014/2015, over 9,000 (>100 x normal) dead Cassin's Auklets were observed on beaches from California to British Columbia
The die‐off was ultimately caused by a reduction in zooplankton prey energy content as a result of the NE Pacific marine heatwave (MHW)
The NE Pacific MHW likely inflated event magnitude by compressing cold‐water habitat, and by proxy live birds, closer to shore than usual
Despite their importance in disease and evolution, highly identical segmental duplications (SDs) are among the last regions of the human reference genome (GRCh38) to be fully sequenced. Using a ...complete telomere-to-telomere human genome (T2T-CHM13), we present a comprehensive view of human SD organization. SDs account for nearly one-third of the additional sequence, increasing the genome-wide estimate from 5.4 to 7.0% 218 million base pairs (Mbp). An analysis of 268 human genomes shows that 91% of the previously unresolved T2T-CHM13 SD sequence (68.3 Mbp) better represents human copy number variation. Comparing long-read assemblies from human (
= 12) and nonhuman primate (
= 5) genomes, we systematically reconstruct the evolution and structural haplotype diversity of biomedically relevant and duplicated genes. This analysis reveals patterns of structural heterozygosity and evolutionary differences in SD organization between humans and other primates.
Peatlands represent large terrestrial carbon banks. Given that most peat accumulates in boreal regions, where low temperatures and water saturation preserve organic matter, the existence of peat in ...(sub)tropical regions remains enigmatic. Here we examined peat and plant chemistry across a latitudinal transect from the Arctic to the tropics. Near-surface low-latitude peat has lower carbohydrate and greater aromatic content than near-surface high-latitude peat, creating a reduced oxidation state and resulting recalcitrance. This recalcitrance allows peat to persist in the (sub)tropics despite warm temperatures. Because we observed similar declines in carbohydrate content with depth in high-latitude peat, our data explain recent field-scale deep peat warming experiments in which catotelm (deeper) peat remained stable despite temperature increases up to 9 °C. We suggest that high-latitude deep peat reservoirs may be stabilized in the face of climate change by their ultimately lower carbohydrate and higher aromatic composition, similar to tropical peats.
PDF
